Oxidation of histamine H1 antagonist mequitazine is catalyzed by cytochrome P450 2D6 in human liver microsomes.
Mequitazine [10-(3-quinuclidinylmethyl) phenothiazine] is a long-acting and selective histamine H1-receptor antagonist that is mainly biotransformed by human liver microsomes to yield hydroxylated and S-oxidized metabolites. Mequitazine hydroxylase was inhibited by propranolol and quinidine. Lineweaver-Burk plots for the hydroxylation and the S-oxidation indicated that the hydroxylation occurred with a low Km (0.72 +/- .26 microM) in human liver microsomes. Microsomes from genetically engineered human B-lymphoblastoid cells expressing cytochrome P450 2D6 (CYP2D6) efficiently metabolized mequitazine to the hydroxylated and S-oxidized metabolites. The results indicate that CYP2D6 isozyme is a major form of CYP responsible for the metabolism of mequitazine in human liver microsomes. Inhibition of CYP3A-catalyzed midazolam 1'-hydroxylase by various histamine H1 antagonists, including mequitazine, suggested that mequitazine and some other histamine H1 antagonists could also be inhibitors of CYP3A in human liver microsomes.
Nakamura
K
K
Division of Drug Metabolism, Hokkaido University, Sapporo 060, Japan.
Yokoi
T
T
Kodama
T
T
Inoue
K
K
Nagashima
K
K
Shimada
N
N
Shimizu
T
T
Kamataki
T
T
D000433:1-Propanol / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002753:Chlorzoxazone / Q000494:pharmacology; D003374:Coumarins / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010615:Phenacetin / Q000494:pharmacology; D010640:Phenothiazines / Q000378:metabolism*; D011233:Precipitin Tests; D013426:Sulfaphenazole / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology
D003374:Coumarins; D004791:Enzyme Inhibitors; D006634:Histamine H1 Antagonists; D010640:Phenothiazines; D013426:Sulfaphenazole; C017299:7-ethoxycoumarin; D002110:Caffeine; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D000433:1-Propanol; D014044:Tolbutamide; C030123:coumarin; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D010615:Phenacetin; D002753:Chlorzoxazone; C006069:mequitazine